Infections with oncogenic types of HPV cause virtually all cases of cervical cancer worldwide. Prophylactic vaccination against HPV 16 and 18, two of the most important HPV types, could protect against a large majority of the cases of cervical cancer globally. Vaccines based on the L1 structural protein of HPV that self-assemble into conformationally-correct virion-like particles (virus-like particles or VLPs) have been shown to be generally safe, immunogenic and effective at preventing precancerous lesions of the cervix associated with HPV-16/18. A community-based Phase 3 randomized controlled trial of an HPV16/18 VLP vaccine is underway in Costa Rica. Costa Rica was chosen for the Phase 3 trial because of our extensive successful scientific collaborations there, the continued high risk of cervical cancer, the universal medical system providing national linkage, and the likelihood of very high participation over the many needed years of close clinical follow-up. Randomization and 3-dose vaccination of 7,466 women enrolled into the HPV-16/18 Vaccine Trial in Costa Rica has been successfully completed. Women have been followed actively on an annual or semi-annual basis since enrollment. Women are now completing their first four years of follow-up in the trial and are being asked to enroll in the extended (up to 10 years) follow-up phase of the study. As women complete four years of active follow-up, cross-over vaccination will be offered to trial participants, as recommended by the trial Data and Safety Monitoring Board (DSMB) and once approved by the Institutional Review Boards (IRBs) overseeing the trial. To date, the trial remains masked. Exploratory analyses are planned and the primary analysis of the prophylactic effect of this vaccine is expected at the end of the first 4-years of follow-up or when sufficient numbers of events occur to warrant evaluation. Evaluation of the therapeutic benefit of this vaccine has been completed. Results from the analysis indicate that the vaccine does not have any effect on clearance of HPV infections, when administered to women who already have an established infection. Thus, the vaccine should not be used to treat established HPV infections or their associated lesions. In support of the vaccine trials, a variety of methodologic and ancillary projects are underway or planned, that will maximize the yield of the main effort. This includes evaluation of immunological correlates of protection, including viral neutralization, total type-specific antibodies, and measures of antibody avidity. Immunological correlates of protection among naturally infected women are being examined and studies are underway to better understand why vaccinated women might be protected against HPV types not included in the vaccine formulation. Several analyses are underway or planned to evaluate the natural history of HPV infection at cervical and other sites and of cervical neoplasia in vaccinated and unvaccinated women.